PB2657: DIFFERENT TYPES OF LEUKEMIAS AND BLEEDING DISORDER DETECTED IN A TURKISH FAMILY WITH GERMLINE RUNX1 MUTATION FOR THE FIRST TIME.
Authors: Pinar Ata, Şenol Demir, Fatma Arikan, Tayfur Toptas, Ahmet Arman
Journal: HemaSphere (2023)

Topic: 33. Bleeding disorders (congenital and acquired) Background: RUNX1 is a transcription factor that is important for hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) characterized by mild to moderate thrombocytopenia leading to prolonged bleeding time and increased risk of developing Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML) or T cell Acute Lymphoblastic Leukemia (T-ALL). Aims: Herein we discussed a germline RUNX1 mutation in a Turkish family with an index case of thrombocytopenia, easy bruising and hypermenorrhea whose mother had Chronic Myeloid Leukemia (CML) with bleeding disorder and grandmother died due to blast crisis of AML. Methods: After evaluation of clinical findings of the index case and family histories, peripheral blood of the proband was screened using a custom designed hemorrhagic malignancy panel (including F8, F9, VWF, ADAMTS13, ITGA2B, ITGB3, GP1BA, GP9, MYH9, ANO6, RUNX1, SLC39A4, SLC30A2, RECQL4, USB1genes) via next-generation sequencing (NGS). Her mother and brother were screened via Sanger Sequencing for the detected mutation. Genomic DNA was extracted from leukocytes using the QIAamp DNA Mini kit. DNA concentrations were measured using Qubit Nanophotometer. Sequencing was performed using the Illumina Miseq platform and confirmations were performed with 3130 Applied Biosystems™ 3130 Genetic Analyzer. Results: A 20 years old female patient with easy bruising, thrombocytopenia and hypermenorrhea was evaluated. At the clinical evaluation there were echymosis areas at both forearm regions and cleft palate. She admitted to our outpatient clinic with hemoglobin 11gr/dL, platelets 117 000 cells/mikroliters, activated prothrombin time (APTT) 28 sc, prothrombin time (PT) 13,4 sc, international normalized ratio (INR) 1. At the thrombocyte aggregation function analysis, there was a low aggregation amplitude and secretion rate at all the agonist assays. After NGS sequencing we detected heterozygote RUNX1 (NM:001001890) c.415C>T (p.Arg139*) mutation. This variant was identified as pathogenic at ClinVar database. According to ACMG guidelines this variant was evaluated as PVS1, PM2 and PP5 reflecting its very strong pathogenicity. The segregation analysis revealed that her mother was also a carrier of the same RUNX1 mutation. Summary/Conclusion: RUNX1 is a transcription factor that has malign transformation effect when there is loss of function mutations present. It has pivotal role in normal physiological hematopoiesis. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) is a genetic disorder related with RUNX1 germline mutations. Herein we presented the first Turkish thrombocytopenia case with germline pathogenic RUNX1 mutation that has also effected family members with acute myeloid leukemia and chronic myeloid leukemia. When bone marrow transplantation is considered, family members must be screened to rule out this type of familial predisposition. Also we detected cleft palate as a minor clinical finding which might be an effect of RUNX1 germline mutation. This finding may expand the clinical spectrum of FPDMM. Keywords: Leukemia, RUNX1, Thrombocytopenia